Choi Ae-Ran, Kim Ju-Hwa, Yoon Sungpil
Research Institute, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, 411-764, Republic of Korea.
Tumour Biol. 2014 Oct;35(10):9831-8. doi: 10.1007/s13277-014-2278-1. Epub 2014 Jul 3.
This study was designed to identify conditions that induce an increase in the sensitivity of drug-resistant cancer cells compared to sensitive cells. Using cell proliferation assays and microscopic observation, thioridazine (THIO) was found to induce higher sensitization in drug-resistant KBV20C cancer cells compared to sensitive KB parent cells. By studying cleaved PARP, annexin V staining, and Hoechst staining, we found that THIO largely increased apoptosis specifically in KBV20C cells, suggesting that the difference in sensitization between the resistant and sensitive cells can be attributed to the ability of THIO to induce apoptosis. THIO could also inhibit p-glycoprotein (P-gp) activity in the resistant KBV20C cells. These observations suggest that the mechanisms underlying THIO sensitization in resistant KBV20C cells involve both apoptosis and P-gp inhibition. Furthermore, co-treatment with THIO and vinblastine (VIB) induces higher sensitization in KBV20C cells than KB cells. As observed in a single treatment with THIO, the sensitization mechanism induced by the co-treatment also involves both apoptosis and P-gp inhibition. These results suggest that the THIO sensitization mechanism is generally conserved. Our findings may contribute to the development of THIO-based therapies for patients presenting resistance to antimitotic drugs.
本研究旨在确定与敏感细胞相比,能诱导耐药癌细胞敏感性增加的条件。通过细胞增殖试验和显微镜观察发现,与敏感的KB亲本细胞相比,硫利达嗪(THIO)能诱导耐药的KBV20C癌细胞产生更高的敏感性。通过研究裂解的PARP、膜联蛋白V染色和Hoechst染色,我们发现THIO主要特异性地增加了KBV20C细胞的凋亡,这表明耐药细胞和敏感细胞之间敏感性的差异可归因于THIO诱导凋亡的能力。THIO还可抑制耐药的KBV20C细胞中P-糖蛋白(P-gp)的活性。这些观察结果表明,THIO使耐药的KBV20C细胞致敏的机制涉及凋亡和P-gp抑制。此外,THIO与长春碱(VIB)联合处理比单独处理THIO在KBV20C细胞中诱导更高的敏感性。正如在单独使用THIO处理时所观察到的,联合处理诱导的致敏机制也涉及凋亡和P-gp抑制。这些结果表明,THIO致敏机制通常是保守的。我们的发现可能有助于为对抗有丝分裂药物耐药的患者开发基于THIO的治疗方法。